title: Distinct sensitivity of CD8+ CD4- and CD8+ CD4+ leukemic cell subpopulations to cyclophosphamide and rapamycin in Notch1-induced T-ALL mouse model.
abstract: The Notch1 signaling pathway plays an essential role in cell growth and differentiation. Over-expression of the intracellular Notch1 domain (ICN1) in murine hematopoietic cells is able to induce robust T-cell acute lymphoblastic leukemia (T-ALL) in mice. Here we explored the drug sensitivity of T-ALL cells in two subpopulations of CD8(+)CD4(+) and CD8(+)CD4(-) cells in Notch1-induced T-ALL mice. We found that Notch1 induced T-ALL cells could be decreased by chemotherapeutic drug cyclophosphamide (CTX). CD8(+)CD4(-) T-ALL cells were more sensitive to CTX treatment than CD8(+)CD4(+) T-ALL cells. The percentage of apoptotic cells induced by CTX treatment was higher in CD8(+)CD4(-) T-ALL cells. T-ALL cells were also inhibited by inhibitor of mTORC1 rapamycin. CD8(+)CD4(+) T-ALL cells were more susceptible to rapamycin treatment than CD8(+)CD4(-) T-ALL cells. Rapamycin treatment selectively arrested more CD8(+)CD4(+) T-ALL cells at G0 phase of cell cycle. A combination of the two drugs significantly improved overall survival of T-ALL bearing mice when compared with CTX or rapamycin alone. These results indicated that CD8(+)CD4(+) and CD8(+)CD4(-) leukemia cell populations had distinct drug sensitivity.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Yingchi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chunlan
authors.initials: C
authors.lastname: Hua
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.forename: Weili
authors.initials: W
authors.lastname: Wang
authors.forename: Sha
authors.initials: S
authors.lastname: Hao
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Yingdai
authors.initials: Y
authors.lastname: Gao
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Zhu
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D051881:Receptor, Notch1; D003520:Cyclophosphamide; D020123:Sirolimus
keywords: Apoptosis; CTX; Cell cycle; Rapamycin; T-ALL